DOI: 10.1148/rg.262055073
RadioGraphics 2006;26:433-451
© RSNA, 2006
Multiple Endocrine Neoplasia: Spectrum of Radiologic Appearances and Discussion of a Multitechnique Imaging Approach1
Andrew F. Scarsbrook, FRCR,
Rajesh V. Thakker, FRCP,
John A. H. Wass, FRCP,
Fergus V. Gleeson, FRCR and
Rachel R. Phillips, FRCR
1 From the Department of Radiology, Churchill Hospital, Oxford Radcliffe NHS Trust, Oxford, England (A.F.S., F.V.G., R.R.P.), and the Academic Endocrine Unit, Nuffield Department of Medicine (R.V.T.) and the Department of Clinical Endocrinology (J.A.H.W.), Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, England. Recipient of Certificate of Merit and Excellence in Design awards for an education exhibit at the 2004 RSNA Annual Meeting. Received March 30, 2005; revision requested May 3 and received June 22; accepted June 23. R.V.T. is supported by the Medical Research Council of England; all remaining authors have no financial relationships to disclose.
Address correspondence to A.F.S., Department of Radiology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, England (e-mail: andyscarsbrook1{at}aol.com).
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Abstract
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Multiple endocrine neoplasia (MEN) is characterized by the occurrence of two or more tumors that may be associated with hyperfunction and malignancy. MEN is caused by genetic defects, and two major types, MEN 1 and MEN 2, are recognized. Each type is characterized by the development of tumors within specific endocrine organs. A multidisciplinary approach involving cooperation between endocrinologists, surgeons, oncologists, and radiologists is pivotal for optimizing patient treatment. Imaging plays a vital role in the diagnosis and management of the disease. To contribute effectively, however, the radiologist must understand the range of anatomic and functional imaging modalities used in the assessment of endocrine disorders. In addition, knowledge of the optimal techniques for evaluating the pituitary, thyroid, parathyroid, pancreatic, adrenal, and foregut carcinoid tumors that occur in these MEN syndromes is essential. Finally, an understanding of the spectrum of disease and of the manifestations of each component is crucial for accurate detection, staging, and surveillance in this diverse patient group.
© RSNA, 2006
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LEARNING OBJECTIVES FOR TEST 4
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After reading this article and taking the test, the reader will be able to:- Recognize the clinical-pathologic features of multiple endocrine neoplasia.
- Describe the imaging manifestations of multiple endocrine neoplasia, with emphasis on characteristic diagnostic features.
- Discuss the role of various imaging modalities in the initial diagnosis and monitoring of multiple endocrine neoplasia.
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Introduction
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Multiple endocrine neoplasia (MEN) comprises various genetically determined disorders with a predisposition to tumor development within two or more components of the endocrine system. There are two major forms of MEN—type 1 (MEN 1) and type 2 (MEN 2)—and each type is characterized by the development of tumors within specific endocrine organs (1). Imaging plays a vital role in the diagnosis and management of the disease. In this article, we describe the various clinical-pathologic features of the MEN syndromes to help increase understanding of disease behavior. In addition, we discuss and illustrate the diverse imaging manifestations of MEN, with special emphasis on characteristic diagnostic features, and the role of different anatomic and functional imaging modalities in the assessment of endocrine organ abnormalities, whether or not MEN is present. We also suggest suitable radiologic protocols for initial diagnosis and monitoring of the disease and briefly discuss the treatment of MEN patients.
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Clinical-Pathologic Features of the MEN Syndromes
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MEN 1
MEN 1, also known as Wermer syndrome, is an autosomal dominant condition with a high penetrance (2). The responsible genetic defect has been identified and is located on chromosome 11 (3). Parathyroid, pancreatic, and pituitary tumors are the major components of the disease (Table 1). Adrenal cortical tumors, carcinoid tumors, lipomatous tumors, and collagenomas may also occur (3–7). Multiple facial angiofibromas occur in 85%–90% of MEN 1 patients, and their presence is highly suggestive of the diagnosis (8). Malignant pancreatic tumors are the major cause of mortality (9).
MEN 2
MEN 2 is also an autosomal dominant cancer syndrome and is characterized by medullary thyroid carcinoma (MTC), benign or malignant pheochromocytomas, and parathyroid hyperplasia or tumors (Table 2) (10). Subclassifications of MEN 2 exist, but all variants have defects within the same gene, which is located on chromosome 10 (10). MTC is common to all variants of MEN 2.
MEN 2B is rare, and most cases involve no family history and are due to a new mutation. All patients with this syndrome have a marfanoid appearance and develop mucosal neuromas, which are pathognomonic for the syndrome. Intestinal ganglioneuromas can occur at any level of the gastrointestinal tract and cause chronic megacolon (11). Rarely, MEN 2 can be associated with Hirschsprung disease (12).
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Imaging in MEN 1
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Parathyroid Imaging
Primary hyperparathyroidism occurs in more than 95% of cases and is the usual presenting feature of MEN 1 (3–7). Typically, the disease affects multiple glands to an extent that may vary widely among glands (13). Parathyroid disease in MEN 2A is also multiglandular but usually has a later onset and a lower associated morbidity. Preoperative imaging has a reduced role in the localization of MEN 1 owing to the need to examine all four glands surgically; however, abnormal ectopic glands are occasionally identified. In addition, imaging plays an important role in patients with persistent hypercalcemia following surgery.
At ultrasonography (US), parathyroid adenomas typically appear as a well-defined, oval hypoechoic mass posterior to the thyroid gland (Fig 1a). Large glands may appear multilobulated or may contain echogenic areas. Between 5% and 15% of parathyroid adenomas are ectopic and may be inaccessible with US (14). US performed by experienced operators has a sensitivity of 82%. CT provides no additional information, except for identifying abnormal ectopic glands within the mediastinum and behind the trachea. Only 50% of mediastinal glands are detected with CT. The use of thin (2–3-mm) sections with a dynamic contrast-enhanced technique maximizes the chances of localization (Fig 1b) (14).
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Figure 1a. Parathyroid imaging in MEN 1: US and computed tomography (CT). (a) Parathyroid adenoma. US image of the neck demonstrates the typical appearance of a parathyroid adenoma in MEN 1: a well-defined, oval hypoechoic mass posterior to the thyroid gland. (b) Parathyroid adenoma in a different patient. Contrast material–enhanced CT scan of the neck shows a right inferior parathyroid adenoma (arrow).
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Figure 1b. Parathyroid imaging in MEN 1: US and computed tomography (CT). (a) Parathyroid adenoma. US image of the neck demonstrates the typical appearance of a parathyroid adenoma in MEN 1: a well-defined, oval hypoechoic mass posterior to the thyroid gland. (b) Parathyroid adenoma in a different patient. Contrast material–enhanced CT scan of the neck shows a right inferior parathyroid adenoma (arrow).
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Magnetic resonance (MR) imaging has a slightly higher sensitivity than CT for the localization of parathyroid masses but is not used as the first-line investigative modality at our institution. Parathyroid adenomas usually have increased signal intensity with T2-weighted and short inversion time inversion-recovery sequences and reduced signal intensity with T1-weighted sequences (Fig 2).
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Figure 2a. Parathyroid imaging in MEN: MR imaging. (a) Parathyroid adenoma. Coronal T2-weighted MR image shows a right parathyroid adenoma with homogeneous high signal intensity (arrow) in the neck. (b, c) Parathyroid adenoma in a patient who presented with persistent hypercalcemia. The patient had previously undergone subtotal parathyroidectomy. (b) Coronal T1-weighted MR image shows a bilobed, low-signal-intensity, left mediastinal parathyroid adenoma (arrow) adjacent to the aortic arch. (c) Corresponding technetium 99m (99mTc)–sestamibi (MIBI) scintigram shows increased radiotracer uptake within the adenoma.
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Figure 2b. Parathyroid imaging in MEN: MR imaging. (a) Parathyroid adenoma. Coronal T2-weighted MR image shows a right parathyroid adenoma with homogeneous high signal intensity (arrow) in the neck. (b, c) Parathyroid adenoma in a patient who presented with persistent hypercalcemia. The patient had previously undergone subtotal parathyroidectomy. (b) Coronal T1-weighted MR image shows a bilobed, low-signal-intensity, left mediastinal parathyroid adenoma (arrow) adjacent to the aortic arch. (c) Corresponding technetium 99m (99mTc)–sestamibi (MIBI) scintigram shows increased radiotracer uptake within the adenoma.
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Figure 2c. Parathyroid imaging in MEN: MR imaging. (a) Parathyroid adenoma. Coronal T2-weighted MR image shows a right parathyroid adenoma with homogeneous high signal intensity (arrow) in the neck. (b, c) Parathyroid adenoma in a patient who presented with persistent hypercalcemia. The patient had previously undergone subtotal parathyroidectomy. (b) Coronal T1-weighted MR image shows a bilobed, low-signal-intensity, left mediastinal parathyroid adenoma (arrow) adjacent to the aortic arch. (c) Corresponding technetium 99m (99mTc)–sestamibi (MIBI) scintigram shows increased radiotracer uptake within the adenoma.
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Parathyroid imaging with 99mTc-MIBI planar and single photon emission CT scintigraphy in which early (15 minutes after radiotracer injection) and delayed (2 hours after injection) images of the neck and mediastinum are obtained has a high sensitivity for the localization of adenomas (Fig 3) (13,15). Subtraction methods with 99mTc-pertechnetate have been used in the past, but this technique has been superseded at most centers. A combination of scintigraphy and US performed by experienced operators has a very high sensitivity for localizing parathyroid disease (16) and is routinely performed at our institution. In difficult cases, such as those involving MEN 1 patients with recurrent hypercalcemia following previous parathyroid surgery, combined anatomic and functional imaging with a CT gamma camera and image coregistration can be the most effective way of localizing residual or recurrent parathyroid adenomas, particularly if they are ectopic (17).
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Figure 3a. Parathyroid imaging in MEN 1: scintigraphy. (a) Parathyroid adenoma. Early (top) and delayed (bottom) 99mTc-MIBI scintigrams show a dominant right superior parathyroid adenoma. All four glands were surgically removed, and the three unaffected glands proved to be hyperplastic. (b) Parathyroid adenomas in a different patient. Early (top) and delayed (bottom) 99mTc-MIBI scintigrams show bilateral parathyroid adenomas.
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Figure 3b. Parathyroid imaging in MEN 1: scintigraphy. (a) Parathyroid adenoma. Early (top) and delayed (bottom) 99mTc-MIBI scintigrams show a dominant right superior parathyroid adenoma. All four glands were surgically removed, and the three unaffected glands proved to be hyperplastic. (b) Parathyroid adenomas in a different patient. Early (top) and delayed (bottom) 99mTc-MIBI scintigrams show bilateral parathyroid adenomas.
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Pancreaticoduodenal Imaging
Most pancreatic tumors in MEN 1 are functional, with less malignant potential than sporadic pancreatic tumors (4). Gastrinomas account for 60% of cases, with major comorbidity due to associated Zollinger-Ellison syndrome (4). Multiple duodenal microgastrinomas (<0.5 cm) account for over one-half of all cases seen in MEN 1 (Fig 4a) (2). Underlying MEN 1 is seen in 25% of sporadic cases of gastrinoma (4). Insulinomas (Fig 4c) account for 30% of islet cell tumors in MEN 1 and coexist with gastrinomas in 10% (6). Other tumor types are rare. A variety of methods have been used to localize pancreaticoduodenal neuroendocrine tumors, including US, CT, MR imaging, venous sampling, somatostatin receptor scintigraphy (SRS), and positron emission tomography (PET) performed with a variety of radiotracers.
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Figure 4a. Pancreaticoduodenal imaging in MEN 1: US. (a, b) Gastrinoma in a patient with hypergastrinemia. (a) Endoscopic US image shows a lesion (arrow) within the duodenal wall. (b) Endoscopic US image shows a focal hypoechoic lesion (arrow) in the pancreatic head. At surgery, the lesion proved to be a gastrinoma. (c) Insulinoma. Intraoperative US image obtained in a patient with a biochemically proved insulinoma but negative cross-sectional imaging findings demonstrates an adenoma (arrow) within the pancreatic body. (Case courtesy of Jane Phillips-Hughes, MD, John Radcliffe Hospital, Oxford, England.)
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Figure 4b. Pancreaticoduodenal imaging in MEN 1: US. (a, b) Gastrinoma in a patient with hypergastrinemia. (a) Endoscopic US image shows a lesion (arrow) within the duodenal wall. (b) Endoscopic US image shows a focal hypoechoic lesion (arrow) in the pancreatic head. At surgery, the lesion proved to be a gastrinoma. (c) Insulinoma. Intraoperative US image obtained in a patient with a biochemically proved insulinoma but negative cross-sectional imaging findings demonstrates an adenoma (arrow) within the pancreatic body. (Case courtesy of Jane Phillips-Hughes, MD, John Radcliffe Hospital, Oxford, England.)
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Figure 4c. Pancreaticoduodenal imaging in MEN 1: US. (a, b) Gastrinoma in a patient with hypergastrinemia. (a) Endoscopic US image shows a lesion (arrow) within the duodenal wall. (b) Endoscopic US image shows a focal hypoechoic lesion (arrow) in the pancreatic head. At surgery, the lesion proved to be a gastrinoma. (c) Insulinoma. Intraoperative US image obtained in a patient with a biochemically proved insulinoma but negative cross-sectional imaging findings demonstrates an adenoma (arrow) within the pancreatic body. (Case courtesy of Jane Phillips-Hughes, MD, John Radcliffe Hospital, Oxford, England.)
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Transabdominal US is usually the first-line investigative modality but has a low sensitivity, with a detection rate of less than 70% (18). Endoscopic US is much more sensitive for the diagnosis of neuroendocrine tumors of the pancreas, with a reported specificity of 95% and a sensitivity of nearly 100% when performed by experienced operators (Fig 4b) (18,19). Islet cell tumors appear as homogeneous hypoechoic masses. However, the technique is invasive, requires an experienced operator, and is available only at specialist centers. In addition, lesions in the distal body or tail may be missed. Intraoperative US is highly effective for identifying pancreatic adenomas, particularly when combined with palpation by the surgeon (Fig 4c) (18).
CT is the most widely used modality for localization. The majority of neuroendocrine tumors of the pancreas and duodenum in MEN 1 are small (<2 cm) and may be multiple; a larger size and the presence of calcification suggest malignancy. The tumors are typically isoattenuating at unenhanced CT and, unless they are large, will not be detected without intravenous administration of contrast material (18,20,21). Typically, the tumors enhance avidly in the arterial phase, but they still may be easily overlooked. Narrowing the window settings enhances detection. Rarely, the tumors can be cystic or appear hypoattenuating relative to normal pancreatic tissue (Fig 5). At our institution, 5-mm sections are obtained prior to intravenous administration of contrast material to localize the pancreas. Then, high-resolution thin sections (1.25 mm) are obtained through the liver and pancreas 25 seconds after injection. Venous phase imaging of the entire upper abdomen is performed after a 50-second delay. Water is used as an oral contrast medium to facilitate visualization of small periampullary lesions.
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Figure 5a. Pancreaticoduodenal imaging in MEN 1: CT. (a) Insulinoma. Contrast-enhanced CT scan shows a partially cystic insulinoma with enhancing walls within the pancreatic head. (b) Adenoma in a different patient. Contrast-enhanced venous phase CT scan shows a small hypoechoic lesion (arrow) within the pancreatic body. Adenomas typically enhance avidly in the arterial phase following contrast material administration and can be missed if imaging is not performed in all three phases.
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Figure 5b. Pancreaticoduodenal imaging in MEN 1: CT. (a) Insulinoma. Contrast-enhanced CT scan shows a partially cystic insulinoma with enhancing walls within the pancreatic head. (b) Adenoma in a different patient. Contrast-enhanced venous phase CT scan shows a small hypoechoic lesion (arrow) within the pancreatic body. Adenomas typically enhance avidly in the arterial phase following contrast material administration and can be missed if imaging is not performed in all three phases.
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CT is also useful in the diagnosis of local spread and liver involvement. Liver metastases are typically hypoattenuating on unenhanced images but enhance avidly in the arterial phase. The overall sensitivity of CT for localizing pancreatic adenomas is 70%–80% (18).
MR imaging has a greater sensitivity than CT for identifying small islet cell tumors (22,23). Relative to normal pancreatic tissue, these tumors have lower signal intensity with T1-weighted sequences and higher signal intensity with T2-weighted sequences. Rarely, a tumor may have a high collagen content, with low signal intensity at T2-weighted imaging and enhancement following intravenous contrast material administration (Fig 6) (24,25). Optimal imaging for maximizing detection should include (a) fat-suppressed spin-and gradient-echo T1-weighted sequences; and (b) fat-suppressed fast spin-echo T2-weighted and dynamic contrast-enhanced fast gradient-echo sequences performed in the arterial, portal venous, and equilibrium phases (22).
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Figure 6a. Pancreaticoduodenal imaging in MEN 1: MR imaging. (a–c) Solitary adenoma (insulinoma). (a) Axial fat-suppressed T1-weighted MR image shows a small low-signal-intensity lesion (arrow) within the pancreatic body. (b) On an axial fat-saturated T2-weighted MR image, the lesion (arrow) demonstrates high signal intensity. (c) Gadolinium-enhanced gradient-echo T1-weighted MR image shows the lesion (arrow) with avid enhancement. The lesion proved to be an insulinoma following surgical excision. (d) Multiple adenomas (insulinomas). Axial T2-weighted MR image obtained in a different patient shows multiple small high-signal-intensity lesions throughout the pancreas. At surgery, these lesions proved to be insulinomas.
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Figure 6b. Pancreaticoduodenal imaging in MEN 1: MR imaging. (a–c) Solitary adenoma (insulinoma). (a) Axial fat-suppressed T1-weighted MR image shows a small low-signal-intensity lesion (arrow) within the pancreatic body. (b) On an axial fat-saturated T2-weighted MR image, the lesion (arrow) demonstrates high signal intensity. (c) Gadolinium-enhanced gradient-echo T1-weighted MR image shows the lesion (arrow) with avid enhancement. The lesion proved to be an insulinoma following surgical excision. (d) Multiple adenomas (insulinomas). Axial T2-weighted MR image obtained in a different patient shows multiple small high-signal-intensity lesions throughout the pancreas. At surgery, these lesions proved to be insulinomas.
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Figure 6c. Pancreaticoduodenal imaging in MEN 1: MR imaging. (a–c) Solitary adenoma (insulinoma). (a) Axial fat-suppressed T1-weighted MR image shows a small low-signal-intensity lesion (arrow) within the pancreatic body. (b) On an axial fat-saturated T2-weighted MR image, the lesion (arrow) demonstrates high signal intensity. (c) Gadolinium-enhanced gradient-echo T1-weighted MR image shows the lesion (arrow) with avid enhancement. The lesion proved to be an insulinoma following surgical excision. (d) Multiple adenomas (insulinomas). Axial T2-weighted MR image obtained in a different patient shows multiple small high-signal-intensity lesions throughout the pancreas. At surgery, these lesions proved to be insulinomas.
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Figure 6d. Pancreaticoduodenal imaging in MEN 1: MR imaging. (a–c) Solitary adenoma (insulinoma). (a) Axial fat-suppressed T1-weighted MR image shows a small low-signal-intensity lesion (arrow) within the pancreatic body. (b) On an axial fat-saturated T2-weighted MR image, the lesion (arrow) demonstrates high signal intensity. (c) Gadolinium-enhanced gradient-echo T1-weighted MR image shows the lesion (arrow) with avid enhancement. The lesion proved to be an insulinoma following surgical excision. (d) Multiple adenomas (insulinomas). Axial T2-weighted MR image obtained in a different patient shows multiple small high-signal-intensity lesions throughout the pancreas. At surgery, these lesions proved to be insulinomas.
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Arterial stimulation and venous sampling can be used when functional tumors are not detected at cross-sectional imaging. This procedure involves selective injection of a secretagogue (eg, calcium) into the arteries supplying the pancreas and simultaneous sampling of hepatic venous blood (Fig 7) (26–28). A rise in the hepatic venous hormone concentration is detected after injection into the artery supplying the tumor. This technique does not have any of the major risks associated with portal venous sampling and can be performed at the same time as pancreatic angiography. It is rarely used as the first-line investigative modality but has a sensitivity of up to 88%, significantly higher than that of angiography alone (28).
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Figure 7. Arterial stimulation and venous sampling in MEN 1. The patient had biochemical evidence of an insulinoma, but no tumor was identified at cross-sectional imaging. Digital subtraction angiogram shows two catheters being used for arterial stimulation and venous sampling. A secretagogue (calcium) is being injected through the catheter on the left side, which lies within the splenic artery. The second catheter lies within the right hepatic vein, where venous sampling is being performed to assess for a rise in hormone concentration following injection. (Courtesy of Philip Boardman, MD, John Radcliffe Hospital, Oxford, England.)
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SRS with indium 111 (111In)–octreotide is a useful second-line investigative modality for radiologically occult neuroendocrine tumors of the pancreas. SRS is a whole-body imaging technique that can provide valuable information concerning the site of metastatic disease, with the capacity to help detect tumors and metastatic deposits as small as 1 cm in diameter (29). Unfortunately, not all pancreatic neuroendocrine tumors express somatostatin receptors, and imaging with this technique may yield false-negative results. The technique has reported sensitivities of 70%–90% and approximately 50% for gastrinomas and insulinomas, respectively (18). Octreotide scintigraphy plays an important role in (a) predicting which patients will respond to radionuclide therapy and (b) monitoring response to therapy.
Despite its increasing role in oncologic imaging, PET does not currently play a major role in the imaging of pancreaticoduodenal neuroendocrine tumors in MEN 1 patients. Most of these tumors are well differentiated and slow growing, with a low metabolic rate; consequently, fluorine 18 (18F) fluoro-2-deoxy-D-glucose (FDG) is not localized within the tumor cells (30). Increased FDG uptake may be seen in more aggressive, poorly differentiated tumors, which are less likely to have somatostatin receptors (31). Other radiotracers such as carbon 11 (11C)–5-hydroxytrypt-amine and copper 64 tetraacetic acid octreotide have been reported to be promising radiopharmaceuticals for PET in patients with neuroendocrine tumors. At present, however, these radiopharmaceuticals are available only at specialist centers (31,32). Although PET may prove to have a greater role in the future, there is currently insufficient evidence to merit its routine use.
Pituitary Imaging
Anterior pituitary adenomas occur in 30% of MEN 1 patients (2). These tumors are usually functioning (60% secrete prolactin, <25% secrete growth hormone, and 5% secrete adrenocorticotropic hormone) (4) and may be the presenting feature of the syndrome in 10% of cases. Conversely, less than 3% of patients with anterior pituitary tumors have underlying MEN 1 (6).
MR imaging is the imaging modality of choice and requires the use of thin-section (
3 mm) sagittal and coronal spin-echo T1-weighted sequences with a small (16–20-cm) field of view. Intravenous administration of gadolinium-based contrast material slightly increases the sensitivity for detecting small adenomas. In patients who cannot undergo MR imaging, contrast-enhanced thin-section (1 mm) CT with sagittal and coronal reformation can be used (33).
Most adenomas are hypointense relative to the normal pituitary gland at cross-sectional imaging, both prior to and following intravenous contrast material administration. A microadenoma may not be clearly visualized, but suggestive signs include focal convexity of the superior margin of the gland and erosion of the sellar floor (Fig 8). Deviation of the pituitary stalk is a nonspecific and unreliable sign. Macroadenomas (>10 mm) may compress adjacent structures. Very rarely, bilateral pituitary adenomas may occur in MEN 1 (34).
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Figure 8a. Pituitary tumor in MEN 1. (a) Coronal T1-weighted MR image shows a left pituitary microadenoma. (b) Sagittal T1-weighted MR image obtained in a different patient shows a pituitary macroadenoma.
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Figure 8b. Pituitary tumor in MEN 1. (a) Coronal T1-weighted MR image shows a left pituitary microadenoma. (b) Sagittal T1-weighted MR image obtained in a different patient shows a pituitary macroadenoma.
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Treatment of pituitary tumors in MEN 1 consists of medical therapy for endocrinopathy or transsphenoidal surgery. Radiation therapy is reserved for residual unresectable tumor (4,5).
Adrenal Imaging
Adrenal lesions are common in MEN 1 and may be asymptomatic in many cases. Up to 40% of patients with MEN 1 have adrenal cortical adenomas, which may rarely be functional and give rise to biochemical abnormalities (4). Adrenal cortical adenomas are typically diagnosed at cross-sectional imaging (CT or MR imaging) and characteristically contain intracellular lipid, which allows a confident diagnosis (Fig 9).
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Figure 9a. Adrenal adenomas in MEN 1. (a) Axial T1-weighted MR image shows bilateral adrenal masses with low signal intensity. (b) Axial out-of-phase MR image shows complete loss of signal intensity within the adrenal masses, a finding that is consistent with benign adrenal cortical adenomas.
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Figure 9b. Adrenal adenomas in MEN 1. (a) Axial T1-weighted MR image shows bilateral adrenal masses with low signal intensity. (b) Axial out-of-phase MR image shows complete loss of signal intensity within the adrenal masses, a finding that is consistent with benign adrenal cortical adenomas.
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Very rarely, adrenal carcinoma can develop in MEN 1. Typically, these tumors are large (>5 cm in diameter); moreover, central necrosis and hemorrhage are common, and there is associated calcification in up to 30% of cases (35). Local invasion, nodal spread, and distant metastases may also be seen (Fig 10).
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Figure 10a. Adrenal carcinoma in MEN 1. (a) CT scan shows a heterogeneous left adrenal mass. The lesion had exhibited progressive enlargement. (b) Contrast-enhanced CT scan reveals multiple enhancing liver lesions, which at biopsy were confirmed to represent metastases from adrenal carcinoma. This neoplasm rarely occurs in MEN 1.
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Figure 10b. Adrenal carcinoma in MEN 1. (a) CT scan shows a heterogeneous left adrenal mass. The lesion had exhibited progressive enlargement. (b) Contrast-enhanced CT scan reveals multiple enhancing liver lesions, which at biopsy were confirmed to represent metastases from adrenal carcinoma. This neoplasm rarely occurs in MEN 1.
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Imaging of MEN 1–associated Carcinoids
Carcinoids develop in approximately 2%–5% of MEN 1 patients and, in contrast with sporadic cases of carcinoid, originate almost exclusively in the foregut, affecting the thymus, bronchus, stomach, and duodenum (3–5). Conversely, less than 4% of patients with a carcinoid also have MEN 1 (36).
MEN 1–associated thymic carcinoids occur predominantly in male patients and typically manifest in middle age, several years after MEN 1 has been diagnosed (37). Thymic tumors are commonly asymptomatic, and many are large at diagnosis (37). The tumors usually behave more aggressively than sporadic carcinoids not associated with MEN 1, and, even with early diagnosis and surgery, cure is uncommon (38). Almost all reported MEN 1–associated carcinoids are hormonally inactive, while over one-half of sporadic tumors are functionally active (38). Underlying MEN 1 may be seen in up to 25% of sporadic cases of thymic carcinoid; to our knowledge, however, there are no reports in the literature of this entity being the presenting feature of the disorder. At radiology, thymic carcinoids typically manifest as a large anterior mediastinal mass (Fig 11), which may be locally invasive and is indistinguishable from a thymoma (37,38). Calcification is relatively common. Many surgeons advocate that prophylactic thymectomy be performed in all MEN 1 patients at the time of subtotal or total parathyroidectomy, although this procedure does not reliably prevent the occurrence of thymic carcinoid due to residual thymic rests (37,38).
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Figure 11a. Thymic carcinoid in MEN 1. Contrast-enhanced chest CT scans obtained in a middle-aged man show an anterior mediastinal mass (a) and multiple pulmonary metastases with concurrent left-sided pneumonia (b).
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Figure 11b. Thymic carcinoid in MEN 1. Contrast-enhanced chest CT scans obtained in a middle-aged man show an anterior mediastinal mass (a) and multiple pulmonary metastases with concurrent left-sided pneumonia (b).
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Bronchial carcinoid has an increased prevalence in MEN 1 and more commonly affects female patients (3–6). Little is known about the natural history of this disorder in MEN 1 patients; however, tumors are usually low grade and have a benign course (39). Rarely, bronchial carcinoids in MEN are more aggressive and may have spread to the liver, bone, or brain at the time of diagnosis (3–6). The cross-sectional appearance of a typical bronchial carcinoid is a spheric or ovoid nodule or mass with well-defined borders, closely related to the central bronchi (Fig 12) (39,40). Up to 30% contain areas of calcification. Atypical bronchial carcinoids are generally larger and more peripheral, may contain central necrosis or hemorrhage, and are more commonly locally invasive (Fig 13) (40).
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Figure 12a. Typical bronchial carcinoid in MEN 1. (a) Contrast-enhanced chest CT scan demonstrates an endobronchial carcinoid (straight arrow) within the right main bronchus, a finding that was detected incidentally during pulmonary artery CT for suspected pulmonary embolic disease. Curved arrow indicates a thrombus within the left inferior pulmonary artery. (b) Coronal reformatted CT image of the chest obtained in a different patient shows a small benign carcinoid (arrow) within the left upper lobe adjacent to a bronchus. (c) On 111In-octreotide scintigrams obtained in the same patient as in b, the tumor demonstrates increased radiotracer uptake.
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Figure 12b. Typical bronchial carcinoid in MEN 1. (a) Contrast-enhanced chest CT scan demonstrates an endobronchial carcinoid (straight arrow) within the right main bronchus, a finding that was detected incidentally during pulmonary artery CT for suspected pulmonary embolic disease. Curved arrow indicates a thrombus within the left inferior pulmonary artery. (b) Coronal reformatted CT image of the chest obtained in a different patient shows a small benign carcinoid (arrow) within the left upper lobe adjacent to a bronchus. (c) On 111In-octreotide scintigrams obtained in the same patient as in b, the tumor demonstrates increased radiotracer uptake.
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Figure 12c. Typical bronchial carcinoid in MEN 1. (a) Contrast-enhanced chest CT scan demonstrates an endobronchial carcinoid (straight arrow) within the right main bronchus, a finding that was detected incidentally during pulmonary artery CT for suspected pulmonary embolic disease. Curved arrow indicates a thrombus within the left inferior pulmonary artery. (b) Coronal reformatted CT image of the chest obtained in a different patient shows a small benign carcinoid (arrow) within the left upper lobe adjacent to a bronchus. (c) On 111In-octreotide scintigrams obtained in the same patient as in b, the tumor demonstrates increased radiotracer uptake.
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Figure 13a. Atypical bronchial carcinoid in MEN 1. (a) Contrast-enhanced chest CT scan shows partial right lower lobe collapse due to a calcified atypical endobronchial carcinoid. An associated pleural effusion is also seen. (b, c) CT scans show pleural deposits (b) and multiple liver metastases (c). (d) Corresponding iodine 123 (123I)–metaiodobenzylguanidine (MIBG) scintigram shows increased radiotracer uptake within the right hemithorax and liver, a finding that is consistent with metastatic disease.
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Figure 13b. Atypical bronchial carcinoid in MEN 1. (a) Contrast-enhanced chest CT scan shows partial right lower lobe collapse due to a calcified atypical endobronchial carcinoid. An associated pleural effusion is also seen. (b, c) CT scans show pleural deposits (b) and multiple liver metastases (c). (d) Corresponding iodine 123 (123I)–metaiodobenzylguanidine (MIBG) scintigram shows increased radiotracer uptake within the right hemithorax and liver, a finding that is consistent with metastatic disease.
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Figure 13c. Atypical bronchial carcinoid in MEN 1. (a) Contrast-enhanced chest CT scan shows partial right lower lobe collapse due to a calcified atypical endobronchial carcinoid. An associated pleural effusion is also seen. (b, c) CT scans show pleural deposits (b) and multiple liver metastases (c). (d) Corresponding iodine 123 (123I)–metaiodobenzylguanidine (MIBG) scintigram shows increased radiotracer uptake within the right hemithorax and liver, a finding that is consistent with metastatic disease.
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Figure 13d. Atypical bronchial carcinoid in MEN 1. (a) Contrast-enhanced chest CT scan shows partial right lower lobe collapse due to a calcified atypical endobronchial carcinoid. An associated pleural effusion is also seen. (b, c) CT scans show pleural deposits (b) and multiple liver metastases (c). (d) Corresponding iodine 123 (123I)–metaiodobenzylguanidine (MIBG) scintigram shows increased radiotracer uptake within the right hemithorax and liver, a finding that is consistent with metastatic disease.
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There is a more than thirtyfold increased prevalence of gastric carcinoid in MEN 1 patients. These tumors occur almost exclusively in MEN 1 patients with a gastrinoma and the associated hypergastrinemic state of Zollinger-Ellison syndrome, affecting up to 40% of this patient group (41). Gastric carcinoids in MEN 1 are multicentric, vary in size, and commonly metastasize to local nodes and the liver (42). Little is known about their malignant potential, but carcinoid syndrome and tumor-related death is rare (4). The appearance of gastric carcinoids at stomach CT or double-contrast upper gastrointestinal examination is frequently striking, with multiple masses associated with diffuse gastric wall thickening (Fig 14) (41).
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Figure 14a. Gastric carcinoids in MEN 1. (a) Axial T2-weighted MR image obtained in a patient with a known gastrinoma and associated Zollinger-Ellison syndrome shows marked gastric wall thickening. (b) Unenhanced CT scan obtained in a different patient shows a solitary nodule arising from the wall of the stomach. This finding is atypical; usually, there are multiple gastric nodules. Biopsy revealed the nodule to be a gastric carcinoid.
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Figure 14b. Gastric carcinoids in MEN 1. (a) Axial T2-weighted MR image obtained in a patient with a known gastrinoma and associated Zollinger-Ellison syndrome shows marked gastric wall thickening. (b) Unenhanced CT scan obtained in a different patient shows a solitary nodule arising from the wall of the stomach. This finding is atypical; usually, there are multiple gastric nodules. Biopsy revealed the nodule to be a gastric carcinoid.
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It is unclear which imaging modality is best for aiding in the early detection of carcinoids. Endoscopy can be used periodically for surveillance in MEN 1 patients with Zollinger-Ellison syndrome. Cross-sectional imaging with CT or MR imaging and functional imaging with radiolabeled MIBG or SRS (since many carcinoids are known to over-express somatostatin receptors) have also been used (42). The advantages of SRS are that (a) it is a whole-body imaging technique, (b) it has been reported to help detect lesions as small as 6 mm that may otherwise be overlooked, and (c) it may demonstrate metastatic disease (Figs 12c, 13d) (42). Thymic carcinoids may be detected at MIBI scintigraphy, but this technique is not widely used (43).
Functional imaging may yield false-negative results and has a slightly lower sensitivity overall than does cross-sectional imaging. For this reason, all MEN 1 patients with proved thymic or bronchial carcinoid should undergo MR imaging for evaluation of disease spread to the bone marrow (38).
MEN 1 patients and asymptomatic gene carriers over the age of 25 years should be screened periodically with cross-sectional imaging to detect these uncommon manifestations of the syndrome. Any MEN 1 patient with a gastric carcinoid should undergo cross-sectional imaging to detect nodal or hepatic metastases. Functional imaging with radiolabeled MIBG or SRS may provide further information about tumor site and metastatic disease. There have been a few small-scale studies regarding the use of PET in the diagnosis of carcinoids of the thymus (44) and gastrointestinal tract (45). In addition, a retrospective study has been conducted comparing FDG PET with SRS and MIBG scintigraphy in localizing metastatic carcinoids (46). However, wider validation is required before PET can be recommended. Carcinoids and any metastatic disease may show similar or variable affinities for different radiotracers; as a result, no one functional test is perfect, and a combination of different imaging modalities helps provide a comprehensive map of disease.
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Imaging in MEN 2
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Thyroid Imaging
MTC occurs in nearly all patients with MEN 2 and at a younger age than does the sporadic form of MTC. Patients may present with ectopic hormone production, and serum calcitonin levels are commonly elevated. Local invasion is common, and nodal spread to the neck and mediastinum occurs in up to 50% of cases (Fig 15) (47). Distant metastases to the liver, lung, and bone occur in 15%–25% of cases (47).
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Figure 15a. MTC in MEN 2. (a, b) Contrast-enhanced CT scans of the neck show a locally invasive thyroid carcinoma with a soft-tissue metastasis (a) and mediastinal lymphadenopathy (b). (c) T2-weighted MR image obtained in a different patient shows multiple liver metastases.
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Figure 15b. MTC in MEN 2. (a, b) Contrast-enhanced CT scans of the neck show a locally invasive thyroid carcinoma with a soft-tissue metastasis (a) and mediastinal lymphadenopathy (b). (c) T2-weighted MR image obtained in a different patient shows multiple liver metastases.
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Figure 15c. MTC in MEN 2. (a, b) Contrast-enhanced CT scans of the neck show a locally invasive thyroid carcinoma with a soft-tissue metastasis (a) and mediastinal lymphadenopathy (b). (c) T2-weighted MR image obtained in a different patient shows multiple liver metastases.
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At cross-sectional imaging (CT or MR imaging), the tumor is solid and may contain calcification. Local, nodal, and distant spread can be readily identified. MTC concentrates radioisotopes that are specific for neuroendocrine tissue, such as 123I-MIBG, pentavalent 99mTc–dimer-captosuccinic acid, and somatostatin analogues such as 111In-octreotide. Thus, scintigraphy facilitates accurate whole-body staging (Fig 16).
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Figure 16a. Metastatic MTC in MEN 2. (a) On an 123I-MIBG scintigram, increased radiotracer uptake due to multiple hepatic metastases is seen within the liver. The scan was used as a baseline image prior to initiating radionuclide therapy with 131I-MIBG. (b) On an 111In-octreotide scintigram obtained in a different patient, multiple areas of increased radiotracer uptake are depicted within the neck, mediastinum, liver, and upper abdomen. (c) Posttreatment 131I-MIBG scintigrams obtained in the same patient as in b show increased radiotracer uptake within the liver due to residual disease.
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Figure 16b. Metastatic MTC in MEN 2. (a) On an 123I-MIBG scintigram, increased radiotracer uptake due to multiple hepatic metastases is seen within the liver. The scan was used as a baseline image prior to initiating radionuclide therapy with 131I-MIBG. (b) On an 111In-octreotide scintigram obtained in a different patient, multiple areas of increased radiotracer uptake are depicted within the neck, mediastinum, liver, and upper abdomen. (c) Posttreatment 131I-MIBG scintigrams obtained in the same patient as in b show increased radiotracer uptake within the liver due to residual disease.
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Figure 16c. Metastatic MTC in MEN 2. (a) On an 123I-MIBG scintigram, increased radiotracer uptake due to multiple hepatic metastases is seen within the liver. The scan was used as a baseline image prior to initiating radionuclide therapy with 131I-MIBG. (b) On an 111In-octreotide scintigram obtained in a different patient, multiple areas of increased radiotracer uptake are depicted within the neck, mediastinum, liver, and upper abdomen. (c) Posttreatment 131I-MIBG scintigrams obtained in the same patient as in b show increased radiotracer uptake within the liver due to residual disease.
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Prevention or cure of MTC is achieved with surgery and is mainly dependent on the accuracy of the first operation. If there are no distant metastases, treatment consists of total thyroidectomy and radical lymph node dissection; however, less aggressive local surgery is indicated if distant spread is identified. Regular postoperative measurement of calcitonin levels is necessary every 6–12 months to detect recurrence. In cases of recurrent disease, cross-sectional imaging and scintigraphy may help guide repeat surgery (local disease only) or radionuclide therapy with 131I-MIBG (123I-MIBG–positive disseminated disease). FDG PET has been shown to be more sensitive than other imaging modalities in detecting metastatic nodal disease (48); however, no single technique provides complete diagnostic certainty. 18F–dihydroxyphenylalanine (DOPA) is a promising new radiotracer for PET, with a higher sensitivity than FDG (63% vs 44%) for lymph node staging in MTC. However, this radiotracer is not yet widely available (49).
Adrenal Imaging
Pheochromocytomas occur in 50% of MEN 2 patients (2). The tumors are bilateral in up to 50% of cases (compared with only 10% of sporadic tumors), and they may be small and asymptomatic at diagnosis. However, almost all lesions have a demonstrable biochemical abnormality (50,51). Malignant transformation is uncommon, occurring in less than 5% of cases (52,53). Rarely, patients may have adrenal medullary hyperplasia with no demonstrable structural abnormality (54).
US has a lower sensitivity than CT or MR imaging for the detection of pheochromocytoma. However, if visualized at US, a pheochromocytoma typically appears as a well-defined, ovoid suprarenal mass that may be heterogeneous because of internal hemorrhage or necrosis (Fig 17a) (50). Unenhanced CT may demonstrate associated speckled calcification in 12% of cases (50). Until relatively recently, iodinated intravenous contrast material was not used in patients with pheochromocytomas owing to the risk of ionic contrast media precipitating a hypertensive crisis. Nonionic intravenous contrast agents do not carry the same risk and can safely be used in pheochromocytoma patients without 
-adrenergic blockage (55). Pheochromocytomas enhance avidly at contrast-enhanced CT following intravenous injection but may appear cystic if there is marked central necrosis (Fig 17b). CT is highly accurate in the detection of these lesions, with a sensitivity of nearly 100%. The use of CT for localization is limited in very thin patients and may be contraindicated in pregnant women (50).
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Figure 17a. Adrenal pheochromocytomas in MEN 2. (a) US image obtained in a patient with MEN 2A demonstrates a heterogeneous right-sided suprarenal mass, a finding that is consistent with a pheochromocytoma. (b) Contrast-enhanced CT scan obtained in a patient with MEN 2B shows bilateral, partially cystic adrenal masses. At surgery, the masses were confirmed to represent pheochromocytomas. Pheochromocytomas in MEN patients are much more likely to be bilateral (50% of cases) compared with sporadic, n | |
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Abstract
LEARNING OBJECTIVES FOR TEST...
